139285

FAM123B

AMER1|OSCS|WTX;family with sequence similarity 123B;FAM123B;family with sequence similarity 123B

Wilms tumor gene on the X chromosome protein|Wilms tumor on the X|adenomatous polyposis coli membrane recruitment 1|protein FAM123B

Xq11.2

protein-coding

Wilms tumor is a pediatric kidney cancer associated with inactivation of the WT1tumor-suppressor gene in 5 to 10% of cases. Using a high-resolution screen for DNA copy-number alterations in Wilms tumor, we identified somatic deletions targeting a previously uncharacterized gene on the X chromosome. This gene, which we call WTX, is inactivated in approximately one-third of Wilms tumors (15 of 51tumors). tumors with mutations in WTX lack WT1 mutations, and both genes share arestricted temporal and spatial expression pattern in normal renal precursors. In contrast to biallelic inactivation of autosomal tumor-suppressor genes, WTX is inactivated by a monoallelic "single-hit" event targeting the single X chromosome in tumors from males and the active X chromosome in tumors from females.

PURPOSE OF REVIEW: We will review the recent (2006/2007) literature on pediatricgenitourinary tumors. RECENT FINDINGS: The WTX gene is now the most common knowngene mutation in Wilms' tumor. It acts as a tumor suppressor gene and may play arole in other malignancies. Current clinical trials have incorporated the loss of heterozygosity of 1p and 16q along with age, tumor size, stage, and response to therapy to risk stratify therapy. The PAX3-FOX01 gene fusion and the IGF-1R-signaling and mTOR-signaling pathways are implicated in rhabdomyosarcoma biology, and hence are promising therapeutic targets for this tumor. SUMMARY: Progress is being made in understanding the pathogenesis of genitourinary tumorsin children, and the prognosis for these children continues to improve. Current treatment strategies are focused on improving event-free survival while decreasing late effects from therapy.

We report on a child with X-linked nephrogenic diabetes insipidus (NDI) who developed Wilms tumor (WT). Nephrogenic diabetes insipidus is caused by mutations of the arginine vasopressin receptor (AVPR2) or aquaporin-II (AQP2) genes. Wilmstumor is also genetically heterogeneous and is associated with mutations of WT1 (15-20%), WTX (20-30%) and other loci. The boy presented at 5 months with failure to thrive, polyuria, hypernatremia and abdominal mass. Analysis of leukocyte DNAshowed a novel missense mutation (Q174H) of the AVPR2 gene, which was not present in his mother. In cells (WitS) isolated from the tumor, WTX mRNA expression and coding sequence were intact. However, we identified a 44-kb homozygous deletion of the WT1 gene spanning exons 4 to 10. The WT1 deletion was not present in leukocyte DNA from the patient or his mother. We also noted strong beta-catenin (CTNNB1) expression in the tumor cells and identified a heterozygote missense Ser45Cys mutation of exon 3 of CTNNB1. However, the mutation was absent both in the constitutional DNA of the patient and his mother. The concurrence of WT and NDI has not been previously reported and may be unrelated. Nevertheless, this case nicely illustrates the sequence of events leading to sporadic Wilms tumor.

Wilms tumor (WT) is one of the most common solid tumors in childhood. mutations in WT1 and CTNNB1 are well established as causal alterations in about 10-15% of cases. Recently, WTX (WT gene on the X-chromosome), a gene implicated in WNT signaling, has been identified as a third WT gene. We determined the mutation status of WTX, CTNNB1, and WT1 in a large set of 429 tumors. Genomic WTX alterations were identified in 17% of WTs, equally distributed between males andfemales. Analysis of 104 WT samples for WTX point mutations revealed a rate of only 2%. An additional 11.5% of tumor samples lacked expression of WTX mRNA. These WTX alterations can occur in parallel to WT1 or CTNNB1 mutations. However,we could not find a significant correlation between WTX deletion status or expression level and clinical parameters suggesting that WTX mutations apparently have little direct impact on tumor behavior and presentation. Incomplete deletions of WTX in several cases suggested heterogeneity in tumors. In a small number of cases, we could analyze separate tumor fragments or microdissected regions with different histology of tumors with heterozygous point mutations. Despite complete allele losses at other sites in the genome, we detected varyingdegrees of WTX mutation. This suggests that WTX alteration is not an essential and early mutation needed to drive tumorigenesis, but rather a later event that may affect only a fraction of cells with unclear clinical relevance.#CI- (c) 2009 Wiley-Liss, Inc.

PURPOSE OF REVIEW: To review the 2008-2009 literature on pediatric genitourinarytumors and highlight the most significant publications. RECENT FINDINGS: New techniques such as gene expression profiling, PET, nephron-sparing surgery, and stem cell transplantation are being incorporated into contemporary treatments for pediatric patients with genitourinary tumors. The WTX gene is the most commonly mutated gene in Wilms tumor, and its product enhances Wilms tumor gene 1-mediated transcription. Germline WTX mutations cause an X-linked sclerosing bone dysplasia but do not appear to predispose to Wilms tumor formation. Protocadherin gene clusters on chromosome 5q31 may act as tumor suppressors. In rhabdomyosarcoma, ILK and platelet-derived growth factor receptor-A join the paired box gene 7 and3-forkhead box O1 fusions as potential therapeutic targets, and muscle-specific microRNAs offer promise as adjuvant therapy. Despite the high cure rate of Wilmstumor, long-term survivors remain at risk of death from various causes. SUMMARY:In general, the prognosis for patients with pediatric genitourinary tumors is favorable. The elucidation of the molecular abnormalities in these tumors is determining risk stratification, treatment strategies, and candidates for new drug development.

PURPOSE: Wilms' tumor (WT), the most common pediatric renal malignancy, is associated with mutations in several well-characterized genes, most notably WT1,CTNNB1, WTX, and TP53. However, the majority of cases do not harbor mutations inthese genes. We hypothesized that additional drivers of tumor behavior would be contained within areas of consistent genomic copy number change, especially those associated with the WT risk groups defined by the International Society of Paediatric Oncology (SIOP). EXPERIMENTAL DESIGN: We analyzed high-resolution (Affymetrix 250K single nucleotide polymorphism array) genomic copy number profiles of over 100 tumors from selected risk groups treated under the SIOP protocols, further characterizing genes of interest by sequencing, Multiplex Ligation-dependent Probe Amplification, or fluorescence in situ hybridization. RESULTS: We identified FBXW7, an E3 ubiquitin ligase component, as a novel Wilms' tumor gene, mutated or deleted in approximately 4% of tumors examined. Strikingly, 3 of 14 (21%) of tumors with epithelial type histology after neoadjuvant chemotherapy had FBXW7 aberrations, whereas a fourth WT patient had germline mutations in both FBXW7 and WT1. We also showed that MYCN copy number gain, detected in 9 of 104 (8.7%) of cases, is relatively common in WT and significantly more so in tumors of the high risk diffuse anaplastic subtype (6 of 19, 32%). CONCLUSIONS: Because MYCN is itself a target of FBXW7-mediated ubiquitination and degradation, these results suggest that a common pathway is dysregulated by different mechanisms in various WT subtypes. Emerging therapies that target MYCN, which is amplified in several other pediatric cancers, may therefore be of value in high risk Wilms' tumor.#CI- Copyright 2010 AACR.

Wilms tumor (WT) accounts for approximately 95 % of ALL pediatric renal tumors, with a peak incidence between 2 and 3 years of age. It occurs in sporadic and congenital forms, the latter often occurring before 1 year of age. Incidence declines with age, and WT rarely is observed in adults. WT is an embryonal tumorof the kidney caused by aberrant proliferation of early metanephric kidney cells. It can arise from more than one developmental error and therefore several subtypes can be defined. WT1, a zinc-finger transcription factor, was identifiedas the first WT gene. Other genes frequently altered somatically in subsets of WT are CTNNB1 and WTX; both genes influence the Wnt signalling pathway. Imprinting alterations of genes in 11p15 are also observed in a subset of WTs. Other pediatric renal tumors occur less often, e.g. malignant rhabdoid tumor of the kidney, clear-cell sarcoma, desmoplastic small-round-cell tumors, congenital mesoblastic nephroma, renal cell carcinoma of childhood, renal primitive neuroectodermal tumors, renal medullary carcinoma, and synovial sarcoma of the kidney. In most of these, characteristic genetic alterations have been identified that help in the unequivocal diagnosis of these childhood renal cancers that areoften difficult to distinguish.

BACKGROUND: Wilms' tumor (nephroblastoma) is the most common pediatric kidney cancer. Only one Wilms' tumor gene is known, WT1 at 11p13, which is mutated in 5% - 10% of Wilms' tumors. Recently, mutations were reported in WTX at Xq11.1 in Wilms' tumors. This study investigated the mutation proportion, type, and distribution in WTX and WT1 in children with Wilms' tumor. The role of WTX/WT1 in the development of Wilms' tumor, and the relationship between clinical phenotypeand genotype, were also studied. METHODS: Wilms' tumor specimens (blood samples from 70 patients and tumor tissue samples from 52 patients) were used. A long fragment of WTX and 10 exons and intron sequences of WT1 were amplified by polymerase chain reaction (PCR) from extracted genomic DNA and sequenced. A chi-square test compared the difference between the WTX mutation group and the no mutation group. The relationship between the mutations and clinical phenotype was analyzed. RESULTS: WTX mutations were found in 5/52 tumor tissues and in 2/70 peripheral blood samples (five cases in total, ALL point mutations). Two patients had a WTX mutation in both samples. WT1 mutations were found in 2/52 tumor tissues and in 4/70 peripheral blood samples (five cases in total, ALL point mutations). One patient had a WT1 mutation in both samples. Ten cases had WTX orWT1 mutation (19.2% of Wilms' tumors). No overlapping WTX and WT1 mutations werefound. No significant differences in clinical parameters were found between patients with and without a WTX mutation. CONCLUSIONS: WTX mutations occur earlyin Wilms' tumor development, but at a low proportion. There was no evidence thatWTX is the main cause of Wilms' tumor. Clinical parameters of patients with WTX mutations are not related to the mutation, indicating a limited impact of WTX ontumor progression. WTX and WT1 mutations occur independently, suggesting a relationship between their gene products.